The constant evolution of analytical instrumentation consists in achieving faster data acquisition and improved instrument sensitivity. In the field of mass spectrometry, structural elucidation of ionized molecules is often carried out using a tandem mass spectrometer, where a particular precursor ion is selected at the first stage of analysis or in the first mass analyzer (MS-1), the precursor ions are subjected to fragmentation (e.g. in a collision cell), and the resulting fragment (product) ions are transported for analysis in the second stage or second mass analyzer (MS-2). The method can be extended to provide fragmentation of a selected fragment, and so on, with analysis of the resulting fragments for each generation. This is typically referred to as MSn spectrometry, with n indicating the number of steps of mass analysis and the number of generations of ions. Accordingly, MS2 corresponds to two stages of mass analysis with two generations of ions analyzed (precursor and products). As but one non-limiting example, tandem mass spectrometry is frequently employed to determine peptide amino acid sequences in biological samples. This information can then be used to identify peptides and proteins.
The procedure of performing tandem mass spectrometry so as to identify a particular analyte is sometimes referred to as selected reaction monitoring (SRM). The act of observing the presence of a particular fragment ion (of a certain product-ion mass-to-charge ratio, m/z) that is generated by fragmentation of a particular chosen and isolated precursor ion (of a certain pre-determined precursor-ion m/z) is, in many instances, powerful evidence of the presence of a particular analyte. The generation of a particular product ion by fragmentation of a selected precursor ion is often referred to as an SRM “transition”. For samples that represent complex mixtures of analytes, each SRM experiment may correspond to an analysis for the presence of and, optionally, the quantity of a particular respective analyte.
A relatively new analysis technique, known as “SWATH MS” has been described for proteome analysis by Gillet et al. (Gillet et al., 2012, Targeted Data Extraction of the MS/MS Spectra Generated by Data-independent Acquisition: A New Concept for Consistent and Accurate Proteome Analysis, Mol. Cell Proteomics 11(6):O111.016717. DOI: 10.1074/mcp.O111.016717.). In the SWATH MS technique, fragment ion spectra are obtained during repeated cycling through sever consecutive precursor isolation windows (swaths). For example, Gillet et al. describe using 32 such precursor isolation windows, each such window 25 Da wide. Such SWATH MS acquisition setup generates, in a single sample injection, time-resolved fragment ion spectra for all the analytes detectable within precursor-ion range m/z range and a user-defined retention time window. The SWATH MS technique also employs a novel data analysis strategy that fundamentally differs from earlier database search approaches. Although Gillet et al. originally described SWATH MS experiments performed using a quadrupole-quadrupole time-of-flight (QqTOF) mass spectrometer system, this data analysis technique may also be employed on a triple-quadrupole mass spectrometer system as illustrated in FIG. 1A described below.
FIG. 1A depicts the components of a conventional mass spectrometer system 1 that may be employed for tandem mass spectrometry. It will be understood that certain features and configurations of the mass spectrometer system 1 are presented by way of illustrative examples, and should not be construed as limiting the implementation of the present teachings in or to a specific environment. An ion source, which may take the form of an electrospray ion source 5, generates ions from an analyte material supplied from a sample inlet. For example, the sample inlet may be an outlet end of a chromatographic column, such as liquid or gas chromatograph (not depicted), from which an eluate is supplied to the ion source. The ions are transported from ion source chamber 10 that, for an electrospray source, will typically be held at or near atmospheric pressure, through several intermediate chambers 20, 25 and 30 of successively lower pressure, to a vacuum chamber 35. The high vacuum chamber 35 houses a quadrupole mass filter (QMF) 51, an ion reaction cell 52 (such as a collision or fragmentation cell) and a mass analyzer 40. Efficient transport of ions from ion source 5 to the vacuum chamber 35 is facilitated by a number of ion optic components, including quadrupole radio-frequency (RF) ion guides 45 and 50, octopole RF ion guide 55, skimmer 60, and electrostatic lenses 65 and 70. Ions may be transported between ion source chamber 10 and first intermediate chamber 20 through an ion transfer tube 75 that is heated to evaporate residual solvent and break up solvent-analyte clusters. Intermediate chambers 20, 25 and 30 and high-vacuum chamber 35 are evacuated by a suitable arrangement of pumps to maintain the pressures therein at the desired values. In one example, intermediate chamber 20 communicates with a port of a mechanical pump (not depicted), and intermediate pressure chambers 25 and 30 and high-vacuum chamber 35 communicate with corresponding ports of a multistage, multiport turbomolecular pump (also not depicted).
Electrodes 80 and 85 (which may take the form of conventional plate lenses) positioned axially outward from the mass analyzer 40 may be used in the generation of a potential well for axial confinement of ions, and also to effect controlled gating of ions into the interior volume of the mass analyzer 40. The mass analyzer 40, which may comprise a quadrupole ion trap, a quadrupole mass filter, a time-of-flight analyzer, a magnetic sector mass analyzer, an electrostatic trap, or any other form of mass analyzer, is provided with at least one detector 49 that generates a signal representative of the abundance of ions that exit the mass analyzer. If the mass analyzer 40 is provided as a quadrupole mass filter, then a detector at detector position as shown in FIG. 1A will generally be employed so as to receive and detect those ions which selectively completely pass through the mass analyzer 40 from an entrance end to an exit end. If, alternatively, the mass analyzer 40 is provided as a linear ion trap or other form of mass analyzer, then one or more detectors at alternative detector positions may be employed.
Ions enter an inlet end of the mass analyzer 40 as a continuous or quasi-continuous beam after first passing, in the illustrated conventional apparatus, through a quadrupole mass filter (QMF) 51 and an ion reaction cell 52. The QMF 51 may take the form of a conventional multipole structure operable to selectively transmit ions within an m/z range determined by the applied RF and DC voltages. The reaction cell 52 may also be constructed as a conventional multipole structure to which an RF voltage is applied to provide radial confinement. The reaction cell may be employed, in conventional fashion, as a collision cell for fragmentation of ions. In such operation, the interior of the cell 52 is pressurized with a suitable collision gas, and the kinetic energies of ions entering the collision cell 52 may be regulated by adjusting DC offset voltages applied to QMF 51, collision cell 52 and lens 53.
The mass spectrometer system 1 shown in FIG. 1A may operate as a conventional triple quadrupole mass spectrometer, wherein ions are selectively transmitted by QMF 51, fragmented in the ion reaction cell 52 (employed as a collision cell), and wherein the resultant product ions are mass analyzed so as to generate a product-ion mass spectrum by mass analyzer 40 and detector 49. Samples may be analyzed using standard techniques employed in triple quadrupole mass spectrometry, such as precursor ion scanning, product ion scanning, single- or multiple reaction monitoring, and neutral loss monitoring, by applying (either in a fixed or temporally scanned manner) appropriately tuned RF and DC voltages to QMF 51 and mass analyzer 40. The operation of the various components of the mass spectrometer systems may be directed by a controller or a control and data system 15, which will typically consist of a combination of general-purpose and specialized processors, application-specific circuitry, and software and firmware instructions. The control and data system 15 may also provide data acquisition and post-acquisition data processing services.
FIG. 1B is a more-detailed depiction of the ion reaction cell 52 showing an entrance electrode 53 disposed at an entrance end 58a of the device and an exit electrode 80 disposed at an exit end 58b. As illustrated, the ion reaction cell comprises a radio-frequency (RF) multipole device—specifically, in this example, a quadrupole—comprising four elongated and substantially parallel rod electrodes arranged as a pair of first rod electrodes 61 and a pair of second rod electrodes 62. The leftmost diagram of FIG. 1B provides a longitudinal view and the rightmost diagram provides a transverse cross-sectional view, respectively, of the ion reaction cell 52. Note that only one of the rod electrodes 62 is shown, since the view of the second rod electrode 62 is blocked in the depicted view. The four rod electrodes define an axis 59 of the device that is, parallel to the rod electrodes 62, 61 and that is centrally located between the rod electrodes; in other words, the four rod electrodes 62, 61 are equidistantly radially disposed about the axis 59.
Although the reaction cell 52 shown in FIG. 1B is illustrated with straight, parallel rod electrodes, alternative reaction cell configurations are known in which the electrodes are curved. Although the reaction cell 52 is shown with four rods so as to generate an RF quadrupolar electric field, the reaction cell may alternatively comprise six (6) rods, eight (8) rods, or even more rods so as to generate a hexapolar, octopolar, or higher-order electric field respectively. The rod electrodes may be contained within a housing 57 which serves to contain a collision gas used for collision induced dissociation of precursor ions introduced into a trapping volume 12 between the rod electrodes 62, 61 through an entrance end 58a. 
FIG. 1C schematically illustrates typical basic electrical connections for the rod electrodes 62, 61. RF modulated potentials provided by power supply 250 are applied to points A and B, which are electrically connected to electrodes 62 and electrodes 61, respectively. The electrode of each pair of electrodes—that is, the pair of electrodes 62 and the pair of electrodes 61—are diametrically opposed to one another with respect to the ion occupation volume 12 that surrounds the longitudinal axis 59. The phase of the RF voltage applied to one of the pairs of electrodes is exactly out of phase with the phase applied to the other pair of electrodes.
In known fashion, application of RF potentials to the rod electrodes 62, 61 as discussed above produces an electric field pseudo-potential well about and in close proximity to the central axis 59. In operation, ion lenses or electrodes, including entrance electrode 53, exit electrode 80 and possibly others (not shown in FIG. 1C) are used to propel ions into the entrance end 58a (FIG. 1B) of the multipolar rod set (e.g., rod electrodes 62, 61) defined by a set of first ends of the plurality of rods. The presence of the RF-generated pseudo-potential well causes the ions to remain in an ion trapping volume in the vicinity of the axis 59 as these ions progress through the reaction cell from the entrance end 58a to an exit end 58b of the multipolar rod set.
The ion trapping volume does not have sharp boundaries that can be precisely located. In any event, however, the true trapping volume lies approximately within the region 12 denoted by lines connecting the innermost points of the four rod electrodes. Thus the region 12 can be considered to comprise a practical trapping volume that is defined by the electrodes themselves such that the true trapping volume resides within the practical trapping volume 12. Both the practical trapping volume and the true trapping volume are elongated parallel to the axis 59 between the entrance end 58a and the exit end 58b. The entrance and exit ends 58a, 58b are defined by the ends of the rod electrodes 62, 61. The ion trapping produced by the application of the RF field is effective in directions that are radial to the axis 59 (that, is within transverse cross-sectional planes such as the one illustrated on the right-hand side of FIG. 1B). In some instances, ions may be temporarily trapped along the dimension parallel to or along the axis 59.
In some instances, the elevated collision gas pressure within a collision cell can cause product ions that have been formed in the collision cell to drain out of the cell slowly or possibly even stall within the collision cell as a result of their very low velocity after many collisions with neutral gas molecules. The resulting lengthened ion clear-out time can cause experimental difficulties when several ion pairs (i.e., parent/products) are being measured in rapid succession. U.S. Pat. No. 5,847,386, in the names of inventors Thomson et al., describes several apparatus configurations that are designed to reduce this problem through the provision of an electric field that is parallel to the device axis within the space between the elongated electrodes.
Another apparatus configuration described in the aforementioned U.S. Pat. No. 5,847,386 includes segmented rods, wherein different DC offset voltages are applied between adjacent segments such that ions within the interior volume experience a stepped DC electrical potential in a direction from the entrance end to the exit end. For example, FIG. 1D illustrates a collision cell or reaction cell 152 in which the rods 62 and the rods 61 (as shown in and previously described in reference to FIG. 1B) are replaced by series of rod segments 161 and 162, respectively. Each of the segments 161 is supplied with the same RF voltage and each segments 162 is supplied with the same phase-shifted RF voltage from power supply 250 via a set of isolating capacitors (not illustrated), but each is supplied with a different DC voltage.
U.S. Pat. No. 7,675,031, in the names of inventors Konicek et al. and assigned to the assignee of the present invention, describes an alternative apparatus configuration to address the problem of slowed ion movement through a collision cell. Konicek et al. teaches the use of auxiliary electrodes for creating drag fields within the cell interior volume. The auxiliary electrodes may be provided as arrays of finger electrodes for insertion between main RF electrodes (e.g., the rod electrodes 62, 61 shown in FIG. 1B) of a multipole device. The finger electrodes may be provided on thin substrate material such as printed circuit board material. A progressive range of voltages can be applied along lengths of the auxiliary electrodes by implementing a voltage divider that utilizes static resisters interconnecting individual finger electrodes of the arrays. Dynamic voltage variations may be applied to individual finger electrodes or to groups of the finger electrodes.
FIG. 1E shows a simplified depiction of one exemplary configuration taught in U.S. Pat. No. 7,675,031. The leftmost view of FIG. 1E is a longitudinal view of the apparatus 252 showing, very schematically, the disposition of auxiliary electrodes 54a-54d, which may be configured with one or more terminal finger electrodes, between the main rod electrodes 62, 61, wherein these rod electrodes are as shown in FIG. 1B. The rightmost view of FIG. 1E is a transverse cross-sectional view which more accurately show how the auxiliary electrodes 54a-54d are disposed between adjacent pairs of the main rod electrodes. The auxiliary electrodes can occupy positions that generally define planes that, if extended, intersect on the central axis 59. These planes can be positioned between adjacent RF rod electrodes at about equal distances from the main RF electrodes of the multipole ion guide device where the quadrupolar fields are substantially zero or close to zero, for example. Thus, the configured arrays of finger electrodes 71 can lie generally in these planes of zero potential or close to zero potential so as to minimize interference with the quadrupolar fields. The array of auxiliary electrodes and finger electrodes can also be adapted for use with curved quadrupolar configurations such as the configuration shown in FIG. 1D.
FIG. 2A illustrates a simplified depiction of one exemplary configuration taught in U.S. Pat. No. 7,675,031. The configuration includes auxiliary electrodes 54a, 54b, 54c, 54d that are configured with one or more finger electrodes 71 and that are designed to be disposed between adjacent pairs of main rod electrodes 61, 62. The relative positioning of the main rod electrodes 61, 62 and auxiliary electrodes 54a, 54b, 54c, 54d in FIG. 2A is somewhat exploded for improved illustration. The auxiliary electrodes can occupy positions that generally define planes whose extensions intersect on the central axis 59, as shown by the directional arrow as referenced by the Roman Numeral III and as also shown in FIG. 1E. These planes can be positioned between adjacent RF rod electrodes 61, 62 at about equal distances from the main RF electrodes of the electrode set where the quadrupolar fields are substantially zero or close to zero, for example. Thus, the configured arrays of finger electrodes 71 can lie generally in these planes of zero potential or close to zero potential so as to minimize interference with the quadrupolar fields. The right-hand side of FIG. 1E shows and end view perspective of the configuration of FIG. 2A, illustrating how the radial inner edges 64a, 64b, 64c, and 64d (see also FIG. 2A) of the finger electrodes 71 may be positioned relative to the main rod electrodes 61 and 62.
Turning back to FIG. 2A, each electrode of the array of finger electrodes 71 may be connected to an adjacent finger electrode 71 by a predetermined resistive element 74 (e.g., a resistor) and in some instances, a predetermined capacitor 77. The desired resistors 74 set up respective voltage dividers along lengths of the auxiliary electrodes 54a, 54b, 54c, 54d. The resultant voltages on the array of finger electrodes 71 thus form a range of voltages, often a range of step-wise monotonic voltages. The voltages create a voltage gradient parallel to the axis 59 that urges ions through the reaction cell 52 from the entrance end 58a to the exit end 58b. In the examples shown in FIGS. 2A-2B, the voltages applied to the auxiliary electrodes often comprise static voltages, and the resistors often comprise static resistive elements. The capacitors 77 reduce an RF voltage coupling effect in which the RF voltages applied to the main RF rod electrodes 61, 62 typically couple to and heat the auxiliary electrodes 54a, 54b, 54c, 54d during operation of the RF rod electrodes 61, 62.
In an alternative configuration taught in U.S. Pat. No. 7,675,031 and as shown in FIG. 2B, one or more of the auxiliary electrodes can be provided by an auxiliary electrode array, as shown generally designated by the reference numeral 130, which has dynamic voltages individually applied to one or more of the array of finger electrodes 71. In this alternative configuration, the controller 15 may include or be augmented by computer controlled voltage supplies 83, 84, 85, which may take the form of Digital-to-Analogue Converters (DACs). There may be as many of these computer controlled voltage supplies 83, 84, 85 as there are finger electrodes 71 in an array, and that each computer controlled voltage supply may be connected to and control a voltage of a respective finger electrode 71 for the array.
As shown in FIG. 2B, and as briefly discussed above, the auxiliary electrode 130, may as one arrangement, have designed voltages applied by a combination of dynamic computer controlled voltage supplies 83, 84, 85 and voltage dividers in the form of static resistors 74 so as to form an overall monotonically progressive range of voltages along a length of a multipole device. In such a configuration, the magnitude and range of voltages may be adjusted and changed to meet the needs of a particular sample or set of target ions to be analyzed. As also shown in FIG. 2B, capacitors 77 may be connected between adjacent finger electrodes 71.
FIG. 2B also shows in detail, the configuration of a radially inner edge 88 that is similar to the radially inner edges 64a, 64b, 64c, 64d, described above for FIG. 2A. The radially inner edge 88 includes a central portion 91 that may be metalized or otherwise provided with a conductive material, tapered portions 92 that straddle the central portion 91, and a recessed gap portion 93. The central portions 91 may be metalized in a manner that connects metallization on both the front and the back of the auxiliary electrode array 130 for each of the finger electrodes 71 of the array of finger electrodes. As an innermost extent of the auxiliary electrode 130, the central portion 91 presents the DC electrical potential in close proximity to the ion path. Gaps 96 including recessed gap portions 93 are needed between metallization of the finger electrodes 71 in order to provide an electrical barrier between respective finger electrodes.
A structural element for receiving and supporting metallization may be a substrate 99, as shown in FIG. 2B, of any printed circuit board (PCB) material, such as, but not limited to, fiberglass, that can be formed, bent, cut, or otherwise shaped to any desired configuration so as to be integrated into the working embodiments of the present invention. Although FIG. 2B shows the substrate as being substantially flat and having straight edges, it is to be understood that the substrates and the arrays of finger electrodes thereon may be shaped with curved edges and/or rounded surfaces. Substrates that are shaped and metalized in this way are relatively easy to manufacture. Thus, auxiliary electrodes in accordance with embodiments of the present invention may be configured for placement between curved main rod electrodes of curved multipoles.
Other Known Methods/Apparatus for Generating Axial or Drag Fields in a Collision Cell
Reference is next made to FIGS. 8A-8D, which show a known modified quadrupole rod set 700 which is modified according to the teachings provided in U.S. Pat. No. 5,847,386 in the names of inventors Thomson et al. The quadrupole rod set 700 comprises a first pair of rods consisting of rods 701 and a second pair of rods consisting of rods 708, both sets of rods equally tapered. The rods 701 of one pair are oriented so that the wide ends 702 of the rods are at the entrance 703 to the interior volume of the rod set, and the narrow ends 704 are at the exit end 705 of the rod set. The rods 708 of the other pair are oriented so that their wide ends 709 are at the exit end 705 of the interior volume and so that their narrow ends 710 are at the entrance 703. The rods define a central longitudinal axis 707.
Each of the rods of 701 and the rods 708 are electrically connected together, with an RF potential applied to each pair (through isolation capacitors C2) by an RF generator 711. A separate DC voltage is applied to each pair, e.g. voltage V1 to the rods 701 and voltage V2 to the rods 708, by DC voltage sources 712a and 712b. The supplied DC voltages provide an axial potential (i.e. a potential on the axis 707) which is different at one end from that at the other end. Thus, an axial field is created along the axis 707. Although a quadrupole rod set is illustrated, the general principles of operation of the modified rod set 700 may be applied to multipole rod sets comprising more than four rods.
FIG. 9 is a side view of two rods of another known rod set configuration 720 as taught in the aforementioned U.S. Pat. No. 5,847,386 and that may be employed to generate an axial field along a central axis 727 of the rod set. The rods are of the rod set 720 are all the same diameter but are oriented such that, at an entrance end 723 of the apparatus, the ends 726 of a first pair of rods, comprising rods 721, are located closer to the central axis 727 than are the opposite ends 724 of the rods 721. In other words, the rods 721 diverge away from the central axis 727 in a direction from the entrance end 723 to the exit end 725 of the quadrupole apparatus. A second pair of rods, comprising rods 728, are oriented such that, at the entrance end 723, the ends 722 are further from the central axis 727 than are the opposite ends 724 of those same rods. Thus, the rods 728 of the second pair converge towards the axis 727 in a direction from the entrance end 723 to the exit end 725. Note that, as in all the other accompanying drawings, the illustration of the rod set 720 is not drawn to scale and thus sizes and angles are exaggerated for clarity.
An alternative non-parallel multipole rod configuration has been described in U.S. Pat. No. 7,985,951 in the name of inventors Okumura et al. and in U.S. Patent Publication No. 2011/0049360 in the name of inventor Schoen. In the above-described rod set 720 (FIG. 9), one set of rods diverges away from a central axis in a direction from an entrance end to an exit end and the other rod set converges towards the central axis in the same direction. In contrast, in the RF-only multipole apparatuses (not illustrated herein) taught in U.S. Pat. No. 7,985,951 and U.S. Publ. No. 2011/0049360, the surfaces of all rods diverge away from the central axis in the direction from the entrance to the exit end. The divergence of the rod surfaces away from the central axis may alternatively be described as an increase in an inscribed radius, r0 (the radius of a circle lying in a radial plane of the multipole that is tangent to the rod inner surfaces), in the same direction. The increase of the inscribed radius, r0, may be most simply accomplished by tilting the long axes of a set of right-circular cylindrical rods such the rod axes diverge from the apparatus central axis in the direction from the entrance to the exit end. The increase of the inscribed radius may also be accomplished by tapering the rods. The divergence of the rod surfaces away from the central axis in the direction of ion travel produces a pseudo-potential gradient that urges ions towards the exit end of the multipole device. This effect may increase the rate at which ions are transported through the multipole device and prevent stalling and unintended trapping of ions. Moreover, by increasing r0 from the inlet end to the exit end of an RF multipole, the value of the Mathieu parameter q of an ion is progressively reduced in the direction of ion travel, resulting in a reduced effective low-mass cutoff and the availability of greater numbers of low-m/z fragment ions for mass analysis.
Similar to the electrical connections shown in FIG. 8B, the rods of 721 of the first rod pair are electrically connected together and the rods of the other (not-illustrated) pair are connected together, with an RF potential applied to each pair by an RF generator. A separate DC voltage is applied to each pair. The supplied DC voltages provide an axial potential (i.e. a potential on the axis 727) which is different at one end from that at the other end. Although a quadrupole rod set is illustrated, the general principles of operation of the modified rod set 720 may be applied to multipole rod sets comprising more than four rods.
FIG. 10 is an end view of a known quadrupole apparatus 730 comprising a set of auxiliary rods or electrodes as taught in the aforementioned U.S. Pat. No. 5,847,386. The four small auxiliary electrodes or rods 732a-732d are mounted parallel to one another and to the quadrupole rods 731, 738 in the spaces between the quadrupole rods. Each of the auxiliary rods 732a-732d has an insulating core 733 with a surface layer of resistive material 734. A voltage applied between the two ends of each auxiliary rod causes a current to flow in the resistive layer, establishing a potential gradient from one end to the other. With all four auxiliary rods connected in parallel, i.e. with the same voltage difference between the ends of the auxiliary rods, the fields generated contribute to the electric field on the central axis 737 of the quadrupole, establishing an axial field or gradient.
FIG. 11 is a side view of another known quadrupole apparatus comprising a set of auxiliary rod electrodes as taught in the aforementioned U.S. Pat. No. 5,847,386. Although the apparatus 740 that is schematically illustrated in FIG. 11 comprises four auxiliary rods, only two such auxiliary rods 742a-742b are shown for clarity. In contrast to the orientation of the auxiliary rods 732a-732d shown in FIG. 10, in which all rods are parallel to the central axis defined by quadrupole rods, the auxiliary rods of the apparatus 740 are tilted, so that they are closer to the central axis 747, as defined by the parallel quadrupole rods 741 and 748, at one end 743 than at the other end 745 of the apparatus. Since the auxiliary rods are closer to the axis at end 743 than at end 745, the potential at end 743 is more affected by the potential on the auxiliary rods than at the other end 745. As a result, an axial potential is generated which varies uniformly from one end to the other since the auxiliary rods are straight. The potential can be made to vary in a non-linear fashion if the auxiliary rods 742a-742b are curved.
The apparatuses described above, comprising conductive rods (either tilted or tapered quadrupole rod electrodes or tilted conductive auxiliary rod electrodes) having different static DC voltages applied to respective different pairs of rods, may disadvantageously give rise to a quadrupole DC field along the central axis. The effect of such a DC field on the properties of an RF-only ion guide may be summarized as the introduction of mass discrimination, whereby the range of ionic mass-to-charge ratios ions that can be transported through a quadrupole ion guide apparatus is reduced. U.S. Pat. No. 6,163,032, in the name of inventor Rockwood, therefore taught the use ion guides in which the number of electrodes are doubled to thereby use symmetry to cancel the undesirable DC quadrupole field. An example of one such apparatus taught in U.S. Pat. No. 6,163,032 is illustrated herewith as FIG. 12.
The modified quadrupole system 750 schematically illustrated in FIG. 12 has twice the number of electrodes 751 than a standard quadrupole system. In the illustrated embodiment, the quadrupole electrode pairs 752 taper in opposite directions. One electrode 751 of the electrode pair 752 tapers from its widest cross section beginning at an arbitrarily selected first end 753 of the system 750 down to its narrowest cross section ending at a second end 755 of the system 750. The other electrode 751 of the electrode pair 752 tapers in the opposite direction and has its narrowest cross section at the first end 753 and widens out to its widest cross section at the second end 755 of the system.
Each electrode 751 of the electrode pair 752 has applied thereto a radio frequency (RF) voltage and a direct current (DC) voltage. Both electrodes 751 of an electrode pair 752 have a same RF voltage applied thereto. However, while electrodes 751 within a same electrode pair have the same polarity, adjacent electrode pairs 752 have applied thereto RF voltages which are always opposite in polarity.
In contrast, DC voltages are applied in order to generate an axial DC electrical field. In order to create an electrical potential between the first end 753 and the second end 755, one electrode 751 of each pair 752 always has a first DC voltage applied thereto, whereas the other electrode of the electrode pair always has a second applied DC voltage. All electrodes 751 having a same cross section width at the first end have the same DC voltage applied thereto in order to generate the axial DC field gradient required to accelerate ions.
FIGS. 13A and 13B schematically illustrate a side view and a cross sectional view of a single rod of a quadrupole or multipole rod set that is modified so as to enable generation of an axial field according to a further teaching of the aforementioned U.S. Pat. No. 5,847,386. Rod 760 is formed as an insulating ceramic tube 762 having on its exterior surface a pair of end metal bands 764 which are highly conductive. Bands 764 are separated by an exterior resistive outer surface coating 766. The inside of tube 762 is coated with conductive metal 768. The wall of tube 762 is relatively thin, e.g. about 0.5 mm to 1.0 mm.
In operation of a multipole apparatus comprising rods 760, a DC voltage difference indicated by V1 is connected to the resistive surface 176 by the two metal bands 174, while the RF from a power supply is connected to the interior conductive metal surface 178. The high resistivity of outer surface 176 restricts the electrons in the outer surface from responding to the RF (which is at a frequency of about 1.0 MHz), and therefore the RF is able to pass through the resistive surface with little attenuation. At the same time voltage source VI establishes a DC gradient along the length of the rod 170, again establishing an axial DC field.
The inventors, Crawford et al., of U.S. Pat. No. 7,064,322 considered that multipole devices that use high resistance multipole rods may be prone to the phenomenon “RF droop” (i.e., areas of reduced RF). The inventors considered that this phenomenon may cause ions to become stalled (and/or filtered) as they are transported through such an ion guide. To counteract this disadvantageous property, the U.S. Pat. No. 7,064,322 teaches the use, in multipole devices, of rods exemplified by the schematic illustration in FIG. 14 herein, wherein each of the rods of the multipole device may be described as containing an inner conductive element 778, an outer resistive element 774, and an insulative element 776 between the inner element 778 and outer element 774. The elements are coaxially arranged along the length of each rod to provide a rod that can be thought of as a coaxial capacitor containing a resistive outer coating. The inner element 778 may optionally be centrally located in the rod (as shown in the uppermost rod of FIG. 14) or optionally present as a layer upon a central core 772 of the rod that provides structural strength (as shown in the lowermost rod of FIG. 14). According to the teachings of U.S. Pat. No. 7,064,322, the insulation and resistive layers do not need to go all the way around the rod, but can be limited to the surface of the rod which influences the ion beam.
FIG. 14 also illustrates exemplary electrical connections between a pair of quadrupole rods 771, such as a pair of rods diametrically opposed to one another across a central axis, according to the teachings of U.S. Pat. No. 7,064,322. In the illustrated embodiment, the resistive element 774 and the conductive element 778 of a rod are electrically connected with each other at one end of the rod. Resistive elements 774 and conductive elements 778 of each of the rods of the rod pair are connected at the same end to the same DC voltage source 773 and the same RF source 775. Likewise, the resistive elements and conductive elements of each of the rods of the other pair of rods (not illustrated in FIG. 14) are connected at the same end to the DC voltage source 773 and the same RF source 775. Resistive element 774 and not conductive element 778 of each rod is connected to DC voltage source 779 and RF source 777 at the other end of each rod. The DC voltage sources 773 and 779 typically supply different DC voltages to the ends of the rods, thereby providing a voltage gradient along the rod. The RF voltage supplied to the ends of each one of the pair of rods 771 by RF sources 775 and 777 is typically in phase, and the RF voltage supplied to the ends of each of the other pair of rods (not shown) by RF sources 775 and 777 is typically in phase. As is known for other multipole devices, the RF voltages supplied to the illustrated rods 771 may be 180 degrees out of phase with that supplied to the other pair of rods.
The inventor, Crawford, of U.S. Pat. No. 7,564,025 determined that a much simpler rod design could be employed in a multipole ion guide device as shown in FIG. 15, in which no conductor is required in the rods and both RF and DC voltages are applied to a resistive material. The accompanying FIG. 15 shows a schematic view of an exemplary rod 780 according to the teachings of U.S. Pat. No. 7,564,025. The rod 780, which need not be cylindrical in cross section, comprises an optional insulating core rod 782 with a resistive coating 786. The resistive coating 786 is usually of small thickness compared with the diameter of core rod 782. The resistive coating 786 need not coat the entire surface of the core rod 782. However, according to the teachings of U.S. Pat. No. 7,564,025, the surface of the rod that faces the axis of the containing multipole device should be covered by the resistive coating.
FIG. 16 is a perspective view of a known ring pole ion transport apparatus as taught in U.S. Pat. No. 6,417,511 in the name of inventor Russ I V et al. The ion transport apparatus 790 illustrated in FIG. 14 comprises a multipole portion 792 and a ring stack portion 794 and has an input end 793 for accepting analyte ions and an output end 795. The ring stack portion 794 extends inside and outside the multipole portion 792, thereby essentially overlapping the multipole portion 792.
The multipole portion 792 of the apparatus 790 comprises a plurality of rods or poles 796 that are grouped together in a spaced apart relationship. The rods 796 may be either parallel or non-parallel to the central axis 797. Further, the rods 796 may have a parallel portion and/or a nonparallel portion. The central axis 797 may be linear or nonlinear, or may have a linear portion and/or a nonlinear portion. The ring stack portion 794 comprises a plurality of rings 798 in a spaced apart stacked relationship distributed along the central axis 797. Each ring 798 of the ring stack portion 794 may comprise a thin, conductive plate. Alternatively, each ring 798 may comprise a thin, nonconductive plate with a conductive coating. Each ring has a generally centrally located inner through-hole 799 to allow passage of ions therethrough. Further, each ring 798 has a plurality of spaced apart through-holes 791, each through hole 791 being dimensioned, positioned and aligned to receive one of the plurality of rods 796 of the multipole portion 792.
In operation, a radio frequency (RF) power source (not shown) is applied to the multipole portion 792 while a direct current (DC) voltage source (not shown) is applied to the ring stack portion 794, such that a respective DC voltage difference is set up between each pair of adjacent rings. The RF power source produces an RF electromagnetic field that functions to “guide” or compress the analyte ions toward a generally centrally located longitudinal axis 797 of the ring pole ion guide 790. The analyte ions, under the influence of the RF power source, travel through the ring pole ion guide 790 in a collimated trajectory, or “beam”. The DC voltage source produces an axial electric field that imparts an accelerating force to the analyte ions. The axial field essentially “pushes” the ions in the transport direction (from the input end 793 to the output end 795) along the central axis 797. Therefore, the multipole portion 792 and its associated RF power source operate in conjunction with the ring stack portion 794 and its associated DC voltage source to simultaneously guide and transport analyte ions from the input end 793 to the output end 795 of the ring pole ion guide 790.
New Requirements to Achieve Fast SRM on a Triple Quadrupole
Fast SRM on a triple quadrupole mass spectrometer such as illustrated in FIG. 1A is a relatively new design goal where the desire is to achieve 500 SRM transitions or more per second. Many presently existing collision cells a purposely designed for high sensitivity. Such designs typically require long internal path lengths and multiple collision conditions that favor complex multistep reaction pathways. Unfortunately, using such a cell that is optimized for sensitivity, the total time required from the selection of a new precursor ion with Q1 to the observation of a stable product signal from Q3 can easily exceed the 2 millisecond total time available for monitoring a specific transition. Even the addition of an axial field (e.g., by employing configurations as shown in FIGS. 1D-1E, FIGS. 2A-2B, FIGS. 8A-8D, FIGS. 9-12, FIGS. 13A-B or FIGS. 14-15) has not proven to be especially useful. Indeed, some reactions have been observed that require 50 milliseconds to reach equilibrium using a collision cell optimized for sensitivity. The operation of such cells may be made faster by employing lower collision pressures and increased RF voltages, but even under these conditions, 0.5 milliseconds may be required to achieve equilibrium.
An alternative design that favors fast reaction pathways is needed for fast SRM. Such a cell may employ a short path length, preferably with an axial field that favors facile reactions that will not require more than a few hundred microseconds to complete. Therefore, fast ion transit times will be acceptable in such shorter cells. However, these short-cell designs will not provide the highest sensitivity in cases where speed is not required. Therefore, the inventors have determined that a two-collision-cell apparatus may be advantageously employed.